Expression profiling reveals fundamental biological differences in acute myeloid leukemia with isolated trisomy 8 and normal cytogenetics

Abstract

Acute myeloid leukemia (AML) is a heterogeneous group of diseases. Normal cytogenetics (CN) constitutes the single largest group, while trisomy 8 (؉8) as a sole abnormality is the most frequent trisomy. How trisomy contributes to tumorigenesis is unknown. We used oligonucleotide-based DNA microarrays to study global gene expression in AML؉8 patients with ؉8 as the sole chromosomal abnormality and AML-CN patients. CD34 ؉ cells purified from normal bone marrow (BM) were also analyzed as a representative heterogeneous population of stem and progenitor cells. Expression patterns of AML patients were clearly distinct from those of CD34 ؉ cells of normal individuals. We show that AML؉8 blasts overexpress genes on chromosome 8, estimated at 32% on average, suggesting gene-dosage effects underlying AML؉8. Systematic analysis by cellular function indicated upregulation of genes involved in cell adhesion in both groups of AML compared with CD34 ؉ blasts from normal individuals. Perhaps most interestingly, apoptosis-regulating genes were significantly down-regulated in AML؉8 compared with AML-CN. We conclude that the clinical and cytogenetic heterogeneity of AML is due to fundamental biological differences.

Outcome after allogeneic transplantation for adult acute myeloid leukemia patients exhibiting isolated or associated trisomy 8 chromosomal abnormality: a survey on behalf of the ALWP of the EBMT

“…2 It is also admitted that the Myc gene located at 8q24 is not a target of þ 8 as Myc in þ 8 AML is down-regulated. 16 Moreover, other data indicated that þ 8 AML showed no specific gene expression signature. 2 In conclusion, our retrospective data show that allo-HSCT is an effective treatment for AML patients harboring þ 8.…”

“…This study suggested also a worsened outcome for these patients in comparison with other cytogenetic abnormality risk group categories within this heterogeneous 'intermediate' prognosis group. 4 Alternatively, patients with þ 8 occurring concomitantly with other cytogenetic aberrations seem to have the prognosis conferred by the accompanying cytogenetic abnormality, at least in the favorable prognosis group ((t(8;21), t(15;17), inv (16)) or when it is observed concomitantly to additional 11q23 aberrations. 1,5,6 Currently, data assessing specifically the role of allo-hematopoietic SCT (HSCT) in the setting of AML with þ 8 are still relatively sparse.…”

Aneuploidy and Cancer: From Correlation to Causation

“…Thus, drug resistance must be polygenic. The same is likely to be true for the other cancer-specific phenotypes such as grossly altered metabolism, invasiveness, metastasis, and immortality [40,45], because all of these phenotypes correlate with altered expressions of thousands of genes [34,87,[116][117][118] and with highly abnormal concentrations of thousands of normal proteins [16,40,51,119]. Moreover, in highly aneuploid cancer cells the number of centrosomes is increased up to 5-fold -from a normal of two to around ten -and at the same time their structures are often altered [120][121][122][123].…”

“…Despite the karyotypic instability and heterogeneity of cancer cells partially specific or nonrandom aneuploidies have been found in cancers since in the late 1960s [61,62,[76][77][78][79][80][81][82][83][84][85][86][87]. Since the 1990s, many more nonrandom aneuploidies have been detected in cancers by the use of comparative genomic hybridization, rather than by identifying specific aneusomies cytogenetically [61,[88][89][90][91][92][93][94][95][96].…”

“…By contrast, the chromosomal theory of cancer explains the complexity of cancer-specific phenotypes by the complexicity of the genetic units that are varied, namely chromosomes with thousands of genes. Accordingly, the complex phenotypes of cancer cells have recently been shown to correlate with over-and underexpressions of thousands of genes [34,87,[116][117][118]136]. Likewise, cancer cells over-and underproduce thousands of normal proteins [16,40,51,119].…”